Abstract
We have developed an antagonist to suppressor of cytokine signaling 1 (SOCS1), pJAK2(1001–1013), which corresponds to the activation loop of the Janus kinase JAK2, which is the binding site for the kinase inhibitory region (KIR) of SOCS1. Internalized pJAK2(1001–1013) inhibits SOCS1 and SOCS3. SOCS1 has been shown to be an influenza virus-induced virulence factor that enhances infection of cells. The antagonist was protective in cell culture and in influenza virus PR8 lethally infected C57BL/6 mice. The SOCS antagonist also prevented adverse morbidity as assessed by parameters, such as weight loss and drop in body temperature, and showed potent induction of both the cellular and humoral immune responses to the influenza virus candidate universal antigen matrix protein 2 (M2e). The SOCS antagonist, thus, protected mice against lethal influenza virus infection and possessed potent adjuvancy against the M2e candidate influenza virus universal vaccine antigen.
Highlights
The process of activation of cells by cytokines, such as the interferons (IFNs), in response to viral infections activates an inducible cytokine regulatory system called suppressors of cytokine signaling (SOCS)
We have shown that the kinase inhibitory region (KIR) sequence of suppressor of cytokine signaling 1 (SOCS1) binds to a peptide corresponding to the phosphorylated activation loop of JAK2, pJAK2(1001–1013), and demonstrated that internalized pJAK2(1001–1013) blocked SOCS1 activity in cells [2, 3]
We have previously shown that pJAK2(1001–1013) antagonized the IFN inhibitory effect of SOCS1 in herpes simplex virus 1 (HSV-1)-infected keratinocytes [7]
Summary
The process of activation of cells by cytokines, such as the interferons (IFNs), in response to viral infections activates an inducible cytokine regulatory system called suppressors of cytokine signaling (SOCS). The N terminus of SOCS1 contains an SH2 domain, and N-terminal to it is an extended SH2 sequence adjacent to a kinase inhibitory region (KIR). These regions or domains of SOCS1 bind to the activation and catalytic regions of JAK2 and block its function. PJAK2(1001–1013) enhances suboptimal IFN activity, blocks SOCS1induced inhibition of STAT3 activation, enhances IFNγ activation site (GAS) promoter activity, and enhances antigen-specific proliferation.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
